SARS-CoV-2 nucleocapsid protein, rather than spike protein, triggers a cytokine storm originating from lung epithelial cells in patients with COVID-19

• Published in: Infection Vol. 52; no. 3; pp. 955 - 983
• Main Authors: Wang, Ying‑Chuan, Tsai, Chih-Hsuan, Wang, Yung-Chih, Yen, Li-Chen, Chang, Yao-Wen, Sun, Jun-Ren, Lin, Te-Yu, Chiu, Chun-Hsiang, Chao, Yu-Chan, Chang, Feng-Yee
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2024; Springer Nature B.V
• Subjects: Coronaviruses; COVID-19; Cytokines; Eotaxin; Epithelial cells; Epithelium; Family Medicine; Fibroblast growth factor 2; Fibroblast growth factors; General Practice; Granulocyte-macrophage colony-stimulating factor; Infectious Diseases; Interleukin 1 receptor antagonist; Interleukin 1 receptors; Interleukin 15; Interleukin 16; Interleukin 2 receptors; Internal Medicine; IP-10 protein; Lungs; Macrophage colony-stimulating factor; Macrophages; Medicine; Medicine & Public Health; Monocyte chemoattractant protein 1; Nerve growth factor; Nucleocapsids; Patients; Platelet-derived growth factor; Platelet-derived growth factor BB; Pneumonia; Proteins; RANTES; Severe acute respiratory syndrome coronavirus 2; Spike protein; Tumor necrosis factor-α; Vascular endothelial growth factor; Viral diseases; COVID-19; SARS-CoV-2; IP-10; Nucleocapsid protein; Cytokine storm
• ISSN: 0300-8126; 1439-0973; 1439-0973
• DOI: 10.1007/s15010-023-02142-4

Purpose The aim of this study was to elucidate the factors associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that may initiate cytokine cascades and correlate the clinical characteristics of patients with coronavirus disease 2019 (COVID-19) with their serum cytokine profiles. Methods Recombinant baculoviruses displaying SARS-CoV-2 spike or nucleocapsid protein were constructed and transfected into A549 cells and THP-1-derived macrophages, to determine which protein initiate cytokine release. SARS-CoV-2-specific antibody titers and cytokine profiles of patients with COVID-19 were determined, and the results were associated with their clinical characteristics, such as development of pneumonia or length of hospital stay. Results The SARS-CoV-2 nucleocapsid protein, rather than the spike protein, triggers lung epithelial A549 cells to express IP-10, RANTES, IL-16, MIP-1α, basic FGF, eotaxin, IL-15, PDGF-BB, TRAIL, VEGF-A, and IL-5. Additionally, serum CTACK, basic FGF, GRO-α, IL-1α, IL-1RA, IL-2Rα, IL-9, IL-15, IL-16, IL-18, IP-10, M-CSF, MIF, MIG, RANTES, SCGF-β, SDF-1α, TNF-α, TNF-β, VEGF, PDGF-BB, TRAIL, β-NGF, eotaxin, GM-CSF, IFN-α2, INF-γ, and MCP-1 levels were considerably increased in patients with COVID-19. Among them, patients with pneumonia had higher serum IP-10 and M-CSF levels than patients without. Patients requiring less than 3 weeks to show negative COVID-19 tests after contracting COVID-19 had higher serum IP-10 levels than the remaining patients. Conclusion Our study revealed that nucleocapsid protein, lung epithelial cells, and IP-10 may be potential targets for the development of new strategies to prevent, or control, severe COVID-19.